Substituted pyrazole sulfonamides



United States Patent This invention relates to novel substitutedpyrazole sulfonamides and alkali metal salts thereof, which have thestructural formula:

where X is selected from the group consisting of pyridyl,p-sulfamylphenyl and p-carboxyphenyl, Y is selected from the groupconsisting of methyl and carboxyl, and Z is selected from the groupconsisting of hydrogen and sulfamyl.

The new compounds in accordance with this invention are usefulchemo-therapeutic agents particularly because of their diureticproperties. The compounds can be administered in therapeutic dosages inconventional vehicles as in the form of a tablet, since they areeffective when administered orally as well as when injected. Since thealkali metal salts of the compounds of this invention are also readilysoluble in an isotonic aqueous medium, injectable solutions can beprepared by dissolving the compound in the selected medium. The alkalimetal salts are stable of themselves, although preservatives may beadded if desired.

The dosage of the substituted pyrazole sulfonamides may be varied over awide range and for this reason, scored tablets containing 100, 150, 250and 500 milligrams of the active ingredient may be made available to thephysician for the symptomatic adjustment of the dosage to the individualpatient. These dosages are well below the toxic or lethal dose of thecompoundv Substituted pyrazole sulfonamides in accordance with thisinvention are readily prepared by reacting the corresponding4-unsubstituted pyrazole with chlorosulfonic acid. The resultingsulfonyl chloride is then reacted with ammonia, producing thesulfonamide.

The alkali metal salts of the compounds of this invention are preparedwith convenience by dissolving the compounds in an aqueous or alcoholicsolution of the selected alkali metal hydroxide and, if desired,isolating the salt by evaporating the solvent. Any of the conventionalalkali metal salts, such as sodium, potassium, lithium or the likesalts, can be prepared by this method or by any other methodsconventionally used and well known to skilled organic chemists.

The preparation of these compounds is more fully described in thefollowing examples. It is to be understood, however, that the examplesare illustrative of the methods employed for their preparation and arenot to be construed as limiting the invention to the particular reactionconditions specifically described. It is to be noted 3,.li3fi i5iPatented Dec. 10, 1963 one of the novel compounds is prepared byreacting a sulfamylphenyl hydrazine with ethyl acetopyruvate to give apyrazole having a sulfamyl-phenyl substituent on the l-nitrogen atom.

EXAMPLE 1 .1- Z-PYRIDY L) -3 ,5 -DIMETi-IYL- PYRAZOLE- i-SULFONAMIDEStep 1.Preparation of I -(2-Pyridyl -3 ,5 -DimethylpyrazoleZ-hydrazinopyridine (8.5 g., 0.078 mole) was added to acetylacetone (8.5g., 0.085 mole) with cooling in a water bath. After 0.5 hour, themixture was distilled in vacuo to obtain 9.2 g. of product, which had aboiling point of 122 C. at 3 mm. pressure.

An analysis of the product showed that it corresponded closely to theempirical formula c H N confirming that the compound was1-(2-pyridyl)-3,5-dirnethylpyrazole.

Step 2.Preparation of 1-(Z-Pyridyl)3,5-Dimethylpyraz0le-4-Sulf0namide Amixture of 7.0 g. (0.04 mole) of l-(2-pyridyl)3,5- dimethylpyrazole and28 g. (0.24 mole) of chlorosulfonic acid was heated 3.5 hours on thesteam bath. The mixture was poured on ice and the precipitated sulfonylchloride was added to 20 cc. of liquid ammonia to give the sulfonamidewhich had a melting point of l59l60 C. when recrystallized fromisopropyl alcohol.

An analysis of the product showed that it corresponded closely to theempirical formula C H N,O S, confirming that the compound wasl-(2-pyridyl)-3,5-dimethylpyrazole-4-sulfonamide.

EXAMPLE 2 .l SULFAMYLPHEI-IYL) -3 5-D METHYLPYRAZOLE-4-SULFONAMIDEl-(p-sulfamylphenyl)-3,5-dimethylpyrazole was prepared by mixingp-sulfamylphenylhydrazine with an excess of acetylacetone. The product,purified by solution in sodium hydroxide solution and precipitation byacid, had a melting point of 230232 C. It was used without furtherpurification.

A mixture of 7.5 g. (0.03 mole) ofl-(p-sulfamylphenyl)-3,5-dimethylpyrazole and 17.5 g. (0.15 mole) ofchlorosulfonic acid was heated 4 hours on the steam bath. The mixturewas poured on ice. Liquid was decanted from the precipitated gum whichwas then dissolved in concentrated ammonium hydroxide. Acidificationafter 15 minutes gave the disulfonamide, M.P. 265-267 C. (fromwater-pyridine mixture).

An analysis of the product showed that it corresponded closely to theempirical formula C H N OgS confirming that the compound wasl-(p-sulfamylphenyl)-3,5-dimethyipyrazole-4-sulfonamide.

EXAMPLE 3 .-l- (p-CARB OXYPHENYL) -3 ,5 -Dl- METHYLPYRAZOLE-l-SULFONAMIDE Step 1.-Preparati0n of 1-(p-Carb0xyphenyl)-3,5-Dimethylpyrazole p-Carboxyphenylhydrazine (40 g., 0.26 mole) wasadded to acetylacetone (30 g., .30 mole). After the exothermic reactionwas finished, the resulting solid cake was dissolved in sodiumbicarbonate solution and the solution acidified to precipitate theproduct, M.P. 151-153 C. (from dilute acetic acid). An analysis of theproduct showed that it corresponded closely to the empirical formula C HN O confirming that the compound was 1- (p-carboxyphenyl) -3 ,5-dimethylpyrazole.

S tep 2.Preparatin of 1 p-C arboxy phenyl -3 ,5 -Dimethylpyrazole-4-Sulf0namide EXAMPLE 4.-5 METHYL 1 (p SULFAMYL- PHENYL)PYRAZOLE-El-CARBOXYLIC ACID The sodium derivative of ethyl acetopyruvatewas prepared according to the procedure described by Marvel and Dregerin Organic Syntheses, collective volume I, p. 238. This salt (18.0 g.,0.1 mole) was dissolved in 100 cc. of 5% sodium hydroxide solution.After minutes the solution was acidified with concentrated hydroch1oricacid and a solution of 18.7 g. (0.1 mole) of p-sulfamylphenylhydrazinein 100 cc. 5% hydrochloric acid was added. The product began toprecipitate immediately and when recrystallized from water-isopropylalcohol had a melting point of 247 C. (decomposition).

An analysis of the product showed that it corresponded closely to theempirical formula C H N O S, confirming that the compound wasS-methyl-l-(p-sulfamylphenyl) pyrazole-3-carboxylic acid.

EXAMPLE 5 set at an initial priming dose of milligrams per kilogram ofbody Weight followed by an infusion of rng/kg/hr. The free compound isalso active when administered orally, only A of the full dose beingrequired, the full oral dose being 30 mg./kg.

Toxicity tests on mice showed the active dose to be far below the lethaldose.,

EXAMPLE 6 Compressed tablet containing 250 milligrams of activeingredient per tablet, in a quantity suitable for fifty tablets:

1- (p sulfamylphenyl)-3,5-dimethylpyrazole-4-sulfonamide and calciumphosphate tribasic are mixed together and then passed twice through No.bolting cloth. The methylcellulose solution is then added and thoroughlymixed in the granulation and the mixture then passed through a No. 10screen. The starch-gelatine solution is ,liaeas then added to thegranulation, thoroughly mixed, and passed through a No. 10 screen afterwhich the total granulation is oven dried at between about to F. for 16to 18 hours, and passed through a No. 18 screen. The methylcellulose ispassed through a No. 60 bolting cloth onto this granulation and blendedthoroughly therewith after which the tale is passed through a No. 60bolting cloth and also thoroughly mixed with the granulation. Theresulting granulation is compressed into tablets having a standardcurvature punch yielding 50 tablets having a thickness of 0.155 to 0.160inch, ten of which weigh 3.321 grams. The tabletshave a hardness of 5 to6 kilograms measured by the Monsanto Chemical Company tablet hardnesstester apparatus, and a disintegration time of 12 minutes when tested bythe U.S.P. tablet disintegrating apparatus (U.S. Pharmacopoeia, 15thedition, p. 937).

EXAMPLE 7 The following is a suitable mixture, showing appropriatequantities per tablet:

The above ingredients are mixed, bolted and compressed into tablets insubstantially the same manner described in Example 6.

EXAMPLE 8 A mixture is prepared as specified in Example 7, using 5-methyl- 1- p-sulfarnylphenyl pyrazole-3 -carboxylic acid in place or"l-(p-carboxyphenyl)-3,5-dimethylpyrazole-4- sulfonamide.

EXAMPLE 9 The compounds prepared in accordance with Examples 14 arelisted in the following table, together with their activities I.V. andthe LD for each.

Effective Compound Dose LD5 (I. V.)

1-(2-pyridyl)-3,5-dirnethylpyra:olel-sullonamide- 1 6001-(p-sullamylphenyl)-3,5-dimethylpyrazole-4-su1- A fonamide M 1621-(p-carhoxyphenyl)-3,5-dimethy1pyrazo fonamid Mo 600 5methyll-(p-sulfamylphcnyl) pyrazole-B-carboxylic acid l4 The activity testsreported in the above table represent that part of a full dose at whichthe compound was active. A full dose is conventionally and arbitrarilyset at an initial priming dose of 25 milligrams per kilogram of bodyweight followed by an infusion of 30 mg./kg./hr. The activity tests wererun in dogs, and the LD were determined in mice.

EXAMPLE 10.1,3 ,5-TRIMETHYLPYRAZOLE-4- SULFONAMIDE I SIO2NH2 HsC lCHaCH:sN-N

1,3,S-trimethylpyrazale (9.3 g., 0.085 mole) was added dropwise during10 minutes to 17.6 g. (0.15 mole) of chlorosulfonic acid. The mixturewas heated on the steam bath for 1.5 hours and then poured on ice. Theprecipitated sulfonyl chloride was collected and converte to thesulfonamide by being added to 20 cc. of concentrated ammonium hydroxide.The sulfonamide when recrystallized from water-isopropyl alcohol had amelting point of 2t)1202 C.

An analysis of the product showed that it corresponded closely to theempirical formula C H N O S, confirming that the compound was1,3,5-trimethylpyrazole-4-sulfcnamide.

EXAMPLE 1 1.4-DIPROPYLSULFAMYL 1 ,3 ,5 TRIMETHYLPYRAZOLE EXAMPLE 12 1 3,5 -D1METHYL-4-PYRAZOLE- SULFONYL) PIPERIDINE moment HNN3,5-dimethylpyrazole (9.6 g., 0.1 mole) was added to 58.5 g.chlorosulfonic acid with ice-bath cooling. The mixture was then heated 3hours on the steam bath. The mixture was cooled and poured on ice andthe solid which separated was added to a solution of g. of piperidine in50 cc. of ether. The solution was extracted with 5% sodium hydroxidesolution. The extract was acidified to precipitate the product whichwhen recrystallized from a 6 benzenecyclohexane mixture had a meltingpoint of 118 119 C.

The analysis corresponds closely to an empirical formula of C H N O S,confirming the product to be the compound named.

While the above examples have described the preparation of certainspecific compounds and a certain specific dosage form suitable foradministering the novel compound of this invention in human therapy, itis to be understood that the invention is not to be limited by theseexamples or by the specific reaction conditions described for thepreparation of the compounds or by the specific ingredients included inthe pharmaceutical preparation. On the contrary, it is understood thatthis invention embraces variations and modifications, including the useof equivalent methods of preparation. However, it is also to beunderstood that this invention is specifically limited to the compoundsdefined in the claim and does not extend to the substitution of anyother groups for those which are specifically defined in the claim.

This application is a division of my copending US. patent applicationSerial No. 804,136, filed by myself on April 6, 1959, now US. Patent No.3,066,137, issued November 27, 1962.

I claim:

1 (p carboxyphenyl) 3,5 -dimethy1pyrazole-4-sulfonamide.

References Cited in the file of this patent UNITED STATES PATENTS FoxSept. 26, 1939 OTHER REFERENCES

